November 26, 2019
As this year comes to a close I’d like to share the significant progress MSRI has made using your generous contributions and explain our current efforts to Find, Stop and Cure Multiple Sclerosis.
MSRI began as a laboratory-based non-profit dedicated to researching the cause and development of MS, the development of new MS therapies and to better understand any potential downsides to them. Since then, we have expanded our laboratory, hired a full-time PhD to work alongside me and purchased state-of-the-art equipment – all due to your thoughtful and generous donations. We continue to advance our research into the regulation of T cells which may help us understand the cause of MS.
We have also recently made significant progress toward understanding the cause of PML, a JC virus brain infection which complicates a number of MS treatments. Our progress here is ground-breaking and we believe our findings will lead to monoclonal antibody therapies which will prevent the development of PML, not only in autoimmune diseases such as MS, but also in non-autoimmune conditions such as leukemia, lymphoma and transplantation. Our research and findings are more fully explained in the attachment to this letter.
Despite our successes, much more needs to be achieved. To build on our results and move toward a cure for MS, we are in desperate need of a cell sorter. Cell sorters are used to identify and isolate individual immune cells for study, and this equipment will help isolate those cells which function inappropriately in MS patients, and which may predispose to the development of this disease. Since MS is an autoimmune condition involving T-cells, state-of-the-art equipment such as a cell sorter which allows us to study these and other immune cells is vital to better understand the cause of MS, discover innovative therapies and develop tests to diagnose and monitor the disease.
Unfortunately, this revolutionary equipment comes at a significant price: $250,000. We have help in this effort in a $50,000 matching contribution which will be applied 1:1 to any contribution made toward this acquisition by the end of this year.
To contribute to this important effort, you can participate in a number of ways:
1. Purchase tickets to, or sponsor, our March 22, 2020, Second-Annual Celebrity Hockey Game and Dinner with Flyers’ Alumni https://msresearchinstitute.org/event/second-annual-celebrity-hockey-game-and-dinner/
3. Purchase a wall tile in the lab at https://msresearchinstitute.org/tile-fundraising-campaign/.
On behalf of all of us at MSRI, as well all MS patients who have benefitted from your generosity, we wish you a happy and healthy holiday season.
Jeffrey I. Greenstein, MD
Main Points of JC Virus Study
Monoclonal antibody (highly uniform and target specific antibody) treatment of MS with Tysabri increases the risk of Progressive Multifocal Leukoencephalopathy (PML) – a JC virus brain infection which complicates Tysabri treatment. The risk of PML is also increased during monoclonal antibody treatment of a wide variety of other autoimmune conditions, as well as conditions such as lymphoma, leukemia and post transplantation. The objective of the study was to determine the extent to which the JC virus infects human peripheral blood lymphocytes (PBMC) in MS and non-MS subjects; and to determine whether Tysabri treatment has an effect on the biology of the virus. The mechanisms by which Tysabri might influence the JC virus and increase the risk for developing (PML) were also investigated.
- JC virus proteins (T Ag, a viral regulatory protein and VP1 a structural viral protein whose presence suggests completion of the viral cycle and potential viral release) can be detected in PBMC in 100% of individuals irrespective of whether they have MS or not; and unrelated to the presence or absence of antibodies against the virus (about 55% of individuals are antibody positive). Along with other studies this is consistent with very early and universal JC virus infection of humans.
- JC virus proteins are found in a greater number of PBMC after Tysabri treatment of MS. B cells (antibody forming cells) and stem cells are responsible for the increased viral protein expression.
- JC viral production is experimentally increased when naturally present virus JC virus is released from PBMC after Tysabri exposure. The released JC virus is transmissible and infectious for susceptible cells which do not normally house the virus. Other types of antibodies have a similar but lesser effect than Tysabri.
- The quantitative release of JC virus with Tysabri stimulation of PBMC is greatest when PBMC are unexposed to Tysabri treatment (in healthy individuals or MS not on Tysabri). While on Tysabri treatment JC virus is released in lesser amounts in the first 5yr of treatment. In contrast there is no additional increase of viral production after 5yr of Tysabri treatment due to a mechanism which breaks down the JC virus proteins.
- Antibody molecules comprise an antigen binding portion (Fab) which binds a specific target (activated PBMC in the case of MS) and another portion of the molecule (Fc) which can attach to immune cells via a receptor on their surface. The Tysabri effect on JC viral production in PBMC is via the Fc portion of the antibody molecule. If this part of the antibody DNA were mutated, Fc binding could be removed, and this could potentially make a monoclonal antibody unlikely to produce PML.
- The intracellular effects of Tysabri on PBMC are being investigated using RNA sequencing which gives a read out of which genes which are affected by Tysabri exposure. This will give a full understanding of our research findings.
These are groundbreaking findings relevant to MS and other conditions, consistent with our mission to solve the important and unsolved problems in MS and MS treatment.